Tissue augmentation material and method

ABSTRACT

A permanent, biocompatible material for soft tissue augmentation. The biocompatible material comprises a matrix of smooth, round, finely divided, substantially spherical particles of a biocompatible ceramic material, close to or in contact with each other, which provide a scaffold or lattice for autogenous, three dimensional, randomly oriented, non-scar soft tissue growth at the augmentation site. The augmentation material can be homogeneously suspended in a biocompatible, resorbable lubricious gel carrier comprising a polysaccharide. This serves to improve the delivery of the augmentation material by injection to the tissue site where augmentation is desired. The augmentation material is especially suitable for urethral sphincter augmentation, for treatment of incontinence, for filling soft tissue voids, for creating soft tissue blebs, for the treatment of unilateral vocal cord paralysis, and for mammary implants. It can be injected intradermally, subcutaneously or can be implanted.

[0001] This application in a continuation of U.S. patent applicationSer. No. 09/626,326, filed Jul. 26, 2000, which is a conversion fromProvisional Application No. 60/148,590, filed Aug. 13, 1999. U.S. patentapplication Ser. No. 09/626,326 is also a continuation-in-part ofApplication No. 09/288,999, filed Aug. 4, 1998, which is a continuationof Application Ser. No. 08/538,444, filed on Oct. 3, 1995 and issued onJul. 13, 1999 as U.S. Pat. No. 5,922,025, which is a division ofApplication Ser. No. 08/159,071, filed Nov. 29, 1993, which is a filewrapper continuation of Application Ser. No. 07/999,411, filed Jan. 21,1993, abandoned, which is a continuation-in-part of Application Ser. No.07/833,874, filed Feb. 11, 1992, abandoned.

FIELD OF THE INVENTION

[0002] This invention relates to biocompatible compositions for softtissue augmentation more specifically urethral sphincter augmentationfor treatment of incontinence, for filling soft tissue voids or creatingsoft tissue blebs, for mammary implants, and for the treatment ofunilateral vocal cord paralysis. This invention also relates to a gelcarrier for the biocompatible compositions.

BACKGROUND OF THE INVENTION

[0003] Examples of biocompatible materials that have been proposed foruse in augmenting soft tissue in the practice of plastic andreconstructive surgery, include collagen, gelatin beads, beads ofnatural or synthetic polymers such as polytetrafluoroethylene, siliconerubber and various hydrogel polymers, such aspolyacrylonitrile-polyacrylamide hydrogels.

[0004] Most often, the biomaterials are delivered to the tissue sitewhere augmentation is desired by means of an injectable compositionwhich comprises the biomaterial and a biocompatible fluid that acts as alubricant to improve the injectability of the biomaterial suspension.The injectable biomaterial compositions can be introduced into thetissue site by injection from a syringe intradermally or subcutaneouslyinto humans or other mammals to augment soft tissue, to correctcongenital anomalies, acquired defects or cosmetic defects. They mayalso be injected into internal tissues such as tissue definingsphincters to augment such tissue in the treatment of incontinence, andfor the treatment of unilateral vocal cord paralysis.

[0005] U.K Patent Application No. 2,227,176 to Ersek et al, relates to amicroimplantation method for filling depressed scars, unsymmetricalorbital floors and superficial bone defects in reconstructive surgeryprocedures using microparticles of about 20 to 3,000 microns which maybe injected with an appropriate physiologic vehicle and hypodermicneedle and syringe in a predetermined locus such as the base ofdepressed scars, beneath skin areas of depression and beneathperichondrium or periosteum in surface irregularities of bone andcartilage. Textured microparticles can be used, including silicone,polytetrafluoroethylene, ceramics or other inert substances. In thoseinstances wherein the requirement is for hard substances, biocompatiblematerial such as calcium salts including hydroxyapatite or crystallinematerials, biocompatible ceramics, biocompatible metals such asstainless steel particles or glass may be utilized. Appropriatephysiological vehicles have been suggested, including saline, variousstarches, polysaccharides, and organic oils or fluids.

[0006] U.S. Pat. No. 4,803,075 to Wallace et al, relates to aninjectable implant composition for soft tissue augmentation comprisingan aqueous suspension of a particulate biocompatible natural orsynthetic polymer and a lubricant to improve the injectability of thebiomaterial suspension.

[0007] U.S. Pat. No. 4,837,285 to Berg et al, relates to acollagen-based composition for augmenting soft tissue repair, whereinthe collagen is in the form of resorbable matrix beads having an averagepore size of about 50 to 350 microns, with the collagen comprising up toabout 10% by volume of the beads.

[0008] U.S. Pat. No. 4,280,954 to Yannas et al, relates to acollagen-based composition for surgical use formed by contactingcollagen with a mucopolysaccharide under conditions at which they form areaction product and subsequently covalently crosslinking the reactionproduct.

[0009] U.S. Pat. No. 4,352,883 to Lim discloses a method forencapsulating a core material, in the form of living tissue orindividual cells, by forming a capsule of polysaccharide gums which canbe gelled to form a shape retaining mass by being exposed to a change inconditions such as a pH change or by being exposed to multivalentcations such as calcium.

[0010] Namiki, “Application of Teflon® Paste for UrinaryIncontinence-Report of Two Cases,” Urol. Int., Vol. 39, pp. 280-282,(1984), discloses the use of a polytetrafluoroethylene paste injectionin the subdermal area to treat urinary incontinence.

[0011] Drobeck et al, “Histologic Observation of Soft Tissue Responsesto Implanted, Multifaceted Particles and Discs of Hydroxylapatite,”Journal of Oral Maxillofacial Surgery, Vol. 42, pp. 143-149, (1984),discloses that the effects on soft tissue of long and short termimplants of ceramic hydroxylapatite implanted subcutaneously in rats andsubcutaneously and subperiosteally in dogs. The inventions consisted ofimplanting hydroxylapatite in various sizes and shapes for time periodsranging from seven days to six years to determine whether migrationand/or inflammation occurred.

[0012] Misiek et al., “Soft Tissue Responses to HydroxylapatiteParticles of Different Shapes,” Journal of Oral Maxillofacial Surgery,Vol. 42, pp. 150-160, (1984), discloses that the implantation ofhydroxylapatite in the form of sharp edged particles or roundedparticles in the buccal soft tissue pouches produced inflammatoryresponse at the implant sites with both particle shapes. Each of theparticles weighed 0.5 grams. However, inflammation resolved at a fasterrate at the sites implanted with the rounded hydroxylapatite particles.

[0013] Shimizu, “Subcutaneous Tissue Responses in Rats to Injection ofFine Particles of Synthetic Hydroxyapatite Ceramic,” BiomedicalResearch, Vol. 9, No. 2, pp. 95-111 (1988), discloses that subcutaneousinjections of fine particles of hydroxyapatite ranging in diameter fromabout 0.65 to a few microns and scattered in the tissue werephagocytized by macrophages in extremely early stages. In contrast,larger particles measuring several microns in diameter were notphagocytized, but were surrounded by numerous macrophages andmultinucleated giant cells. It was also observed that the small tissueresponses to hydroxyapatite particles were essentially a non-specificforeign body reaction without any cell or tissue damage.

[0014] R. A. Appell, “The Artificial Urinary Sphincter and PeriurethralInjections,” Obstetrics and Gynecology Report Retort Vol. 2, No. 3, pp.334-342, (1990), is a survey article disclosing various means oftreating urethral sphincteric incompetence, including the use ofinjectables such as polytetrafluoroethylene micropolymer particles ofabout 4 to 100 microns in size in irregular shapes, with glycerin andpolysorbate. Another periurethral injectable means consists of highlypurified bovine dermal collagen that is crosslinked with glutaraldehydeand dispersed in phosphate-buffered physiologic saline.

[0015] Politano et al, “Periurethral Teflon®Injection for UrinaryIncontinence,” The Journal of Urology, Vol. 111, pp. 180-183 (1974),discloses the use of Polytetrafluoroethylene paste injected into theurethra and the periurethral tissues to add bulk to these tissues torestore urinary control in both female and male patients having urinaryincontinence.

[0016] Malizia et al, “Migration and Granulomatous Reaction AfterPeriurethral Injection of Polytef (Teflon®),” Journal of the AmericanMedical Association, Vol. 251, No. 24, pp. 3277-3281, Jun. 22-29 (1984),discloses that although patients with urinary incontinence have beentreated successfully by periurethral injection ofpolytetrafluoroethylene paste, a study in continent animals demonstratesmigration of the polytetrafluoroethylene particles from the inspectionsite.

[0017] Claes et al, “Pulmonary Migration Following PeriurethralPolytetrafluoroethylene Injection for Urinary Incontinence,” The Journalof Urology, Vol. 142, pp. 821-22, (September 1989), confirms the findingof Malizia in reporting a case of clinically significant migration ofpolytetrafluoroethylene paste particles to the lungs after periurethralinjection.

[0018] Ersek et al, “Bioplastique: A New Textured CopolymerMicroparticle Promises Pennanence in Soft-Tissue Augmentation,” Plasticand Reconstructive Surgery, Vol. 87, No. 4, pp. 693-702, (April 1991),discloses the use of a biphasic copolymer made of fully polymerized andvulcanized methylmethylpolysiloxane mixed with a plasdone hydrogel, andused in reconstructing cleft lips, depressed scars of chicken pox andindentations resulting from liposuction, glabella frown wrinkles andsoft tissue augmentation of thin lips. The biphasic copolymer particleswere found to neither migrate nor become absorbed by the body weretextured and had particle sizes varying from 100 to 600 microns.

[0019] Lemperle et al. “PMMA Microspheres for Intradermal Implantation:Part I. Animal Research,” Annals of Plastic Surgery, Vol. 26, No. 1, pp.57-63, (1991), discloses the use of polymethylmethacrylate microsphereshaving particle sizes of 10 to 63 microns in diameter used forcorrection of small deficiencies within the dermal corium to treatwrinkles and acne scars.

[0020] Kresa et al, “Hydron Gel Implants in Vocal Cords,” OtolarynologyHead and Neck Surgery, Vol. 98. No. 3, pp. 242-245, (March 1988),discloses a method for treating vocal cord adjustment where there isinsufficient closure of the glottis which comprises introducing a shapedimplant of a hydrophilic gel that has been previously dried to a glassy,hard state, into the vocal cord.

[0021] Hirano et al, “Transcutaneous Intrafold Injection for UnilateralVocal Cord Paralysis: Functional Results,” Ann. Otol. Rhinol. Laryngol.,Vol. 99, pp. 598-604 (1990), discloses the technique of transcutaneousintrafold silicone injection in treating glottic incompetence caused byunilateral vocal fold paralysis. The silicone injection is given under alocal anesthetic with the patient in a supine position, wherein theneedle is inserted through the cricothyroid space.

[0022] Hill et al, “Autologous Fat Injection for Vocal CordMedialization in the Canine Larynx,” Laryngoscope, Vol. 101, pp. 344-348(April 1991), discloses the use of autologous fat as an alternative toTeflon®collagen as the implantable material in vocal cord medialization,with a view to its use as an alternative to non-autologous injectablematerial in vocal cord augmentation.

[0023] Mikaelian et al, “Lipoinjection for Unilateral Vocal CordParalysis,” Laryngoscope, Vol. 101, pp. 4654-68 (May 1991), disclosesthat the commonly used procedure of injecting Teflon®paste to improvethe caliber of voice in unilateral vocal cord paralysis has a number ofdrawbacks, including respiratory obstruction from overinjected Teflon®and unsatisfactory voice quality. In this procedure, lipoinjection offat commonly obtained from the abdominal wall appears to impart a softbulkiness to the injected cord while allowing it to retain its vibratoryqualities. The injected fat is an autologous material which can beretrieved if excessively overinjected.

[0024] Strasnick et al, “Transcutaneous Teflon® Injection for UnilateralVocal Cord Paralysis: An Update,” Laryngoscope, Vol. 101, pp. 785-787(July 1991), discloses the procedure of Teflon® injection to restoreglottic competence in cases of paralytic dysphonia.

SUMMARY OF THE INVENTION

[0025] In accordance with the present invention, there is provided apermanent, biocompatible material for soft tissue augmentation, andmethods for its use. There is also provided in accordance with thepresent invention a gel carrier which is particularly advantageous forthe administration of the biocompatible material to the desired tissueaugmentation site.

[0026] The biocompatible material comprises a matrix of smooth, rounded,substantially spherical, finely divided particles of a biocompatibleceramic material, close to or in contact with each other, which providea scaffold or lattice for autogenous, three dimensional, randomlyoriented, non-scar soft tissue growth at the augmentation site. Theaugmentation material can be homogeneously suspended, for example, in abiocompatible, resorbable lubricious gel carrier comprising, e.g., apolysaccharide. This serves to improve the delivery of the augmentationmaterial by injection to the tissue site where augmentation is desired.The augmentation material is especially suitable for urethral sphincteraugmentation, for treatment of incontinence, for filling soft tissuevoids, for creating soft tissue blebs, for the treatment of unilateralvocal cord paralysis, and for mammary implants. It can be injectedintradermally or subcutaneously or can be implanted.

DESCRIPTION OF THE DRAWINGS

[0027] In the accompanying drawings,

[0028]FIG. 1 is a photomicrograph of smooth, round calciumhydroxyapatite particles at 40× magnification;

[0029]FIG. 2 is a photomicrograph of a histological section of rabbittissue at 50× magnification showing fibroblastic infiltration.

[0030]FIG. 3 is a graph of the viscosity of the gel and augmentationmedia both before and after sterilization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] In instances of urinary incontinence, such as stress incontinencein women, or after a prostatectomy in men, it is necessary to compressthe urethra to assist the sphincter muscle in closing to avoid leakageof urine from the bladder.

[0032] The soft tissue augmentation material of the present inventioncomprises an injection system which can be used to add bulk and localizecompression to the sphincter muscle/urethra, thereby reducing the lumensize through one or more injections of the augmentation material andthus substantially reduce or eliminate urinary stress incontinence dueto incompetent sphincters in females and males.

[0033] The augmentation material can also be used in filling andsmoothing out soft tissue defects such as pock marks or scars. Furtheruse for the augmentation material can be for intracordal injections ofthe laryngeal voice generator by changing the shape of this soft tissuemass. The procedure involves delivering the augmentation material to thesite of treatment, preferably by injection. The augmentation material orgel can also be used for mammary implants.

[0034] The inventive augmentation material comprises smooth rounded,substantially spherical, particles of a ceramic material. The term“substantially spherical” refers to the fact that while some of thepresent particles may be spheres, most of the particles of the presentinvention are sphere-like in their shape, i.e., they are spheroidal.FIG. 1 is illustrative of these spheroidal or substantially sphericalcharacteristics. The terms “rounded” or “smooth, rounded” as used hereinrefers to the fact even though the present particles are not perfectspheres, they do not have any sharp or angular edges. The particles mustbe sufficiently large so as to avoid phagocytosis, as is furtherdiscussed below. As an upper limit the particles can be any sizesuitable for the desired soft tissue augmentation. However, it isunderstood that for introduction by injection the upper limit onparticle size will be dictated by the particular injection equipmentemployed. That is, the particles must be sufficiently small so as toavoid aggregation and clogging of the syringe when being injected. Atypical range for injection is from about 35 to 150 microns, preferablyin a narrow particle size range extending not more than about 35microns, and more preferably extending not more than about 10 to 30microns, and-most preferably having substantially equivalent particlesizes. For example, the ceramic material can have a uniform particlesize distribution of about 35 to 65 microns, or 75 to 100 microns or 100to 125 microns. These are meant to be exemplary and not limiting. Othernarrow particle size ranges within the overall size range of 35 to 150microns can also be used. In discussing these ranges, it should beunderstood that as a practical matter, a small amount of particlesoutside the desired range may be present in a sample of the presentaugmentation material. However, most of the particles in any givensample should be within the desired range. Preferably, 90% of theparticles are within the desired range and most preferably 95-99% arewithin the range.

[0035] The finely divided ceramic augmentation material is substantiallynon-resorbable so that repetitious corrections are not necessary. Bysubstantially non-resorbable” is meant that although some dissolution ofthe augmentation material may take place over time, it is sufficientlyslow so as to allow for replacement with growing tissue cells. There isno antigenic response because there are no amino acids as in collagenand fibrinogen. The ceramic material is highly biocompatible and can beinjected through an 18 gauge or smaller opening syringe.

[0036] The preferred ceramic material is calcium hydroxyapatite, alsoknown as basic calcium orthophosphate, or calcium hydroxylapatite, andis the natural mineral phase of teeth and bones. As an implant material,granular calcium hydroxyapatite, which is a sintered polycrystallinecomposite of calcium phosphate, has proven to be highly compatible intissue.

[0037] One method for preparing dense, rounded or substantiallyspherical ceramic particles such as calcium hydroxyapatite is by spraydrying a slurry of about 20 to 40 weight % submicron particle sizecalcium hydroxyapatite. This material is commercially available or canbe prepared by means known in the art such as by low temperaturecrystallization methods, hydrothermal crystallization methods,solid-solid reaction and the like. The slurry can also includeprocessing additives such as wetting agents and binders, on the order ofabout 1 to 5 weight %. Suitable wetting agents include polysorbate,sodium oxalate, ammonium polyelectrolyte. Suitable binders includepolyvinyl alcohol, dextrin or carbowax.

[0038] The slurry is spray dried by pumping it through a nozzle to formglobules that are forced through a column of heated air to remove themoisture. The agglomerated particles dry in substantially sphericalshape and are collected at one end of the heated column.

[0039] The substantially spherical particles are then sintered in acrucible at temperatures of about 1050 to 1200° C. for at least onehour. To minimize further agglomeration, a presintering operation atabout 800 to 1000° C. for about one hour can be employed.

[0040] After the presintering operation, the globular particles can beagitated or rolled to prevent the individual particles from sticking orclumping together. A rotary calcining furnace can be used for thispurpose. This type of furnace rotates so that the agglomerated particlesroll over one is another during the sintering process thereby minimizingthe clumping together of the particles. A commercial source of suchspray dried particles is CeraMed Corp., Lakewood, Colo.

[0041] An alternative method for forming dense, spherical particles isby rotary agglomeration, wherein the fine, submicron ceramic particles,such as calcium hydroxyapatite, are placed on a large diameter rotatingbowl that is at least about 3 feet in diameter.

[0042] The bowl is rotated on its axis at an angle of approximatelythirty degrees, with its speed and angle of rotation adjusted so thatthe submicron particles roll across the face of the bowl. A fine sprayof binder solution, such as those described above, is then sprayed onthe particles at a rate which just wets the particles. The rollingaction across the face of the bowl and the addition of the bindersolution causes the particles to form small rolling agglomerates thatgrow in size as the operation continues. The operation is comparable toforming a large ball of snow by rolling a small snowball down a hill.The operating conditions, such as the size of bowl, speed of rotation,angle of rotation and amount of spray used which define the size anddensity of the agglomerates formed, are well known to those skilled inthe art. The agglomerated spherical particles can then be sintered in amanner similar to the spray dried agglomerates.

[0043] The resulting sintered spherical particles can then be separatedand classified by size by means of well known sieving operations throughspecifically sized mesh screens. The particle size distribution anddensity can also be evaluated to ensure suitability for a particularapplication. A commercial source of such rotary agglomerated particlesis CAM Implants, Leiden, The Netherlands.

[0044] Further surface refining or smoothing can be accomplished by amilling operation, such as ball milling. Extra mini-grinding media canbe used, but to minimize contamination, the spherical particles can bemilled on themselves. This can be done in a standard jar mill or aninclined rotation mill by adding sufficient amounts of purified water tothe particles to ensure that the particles roll evenly over each other.This can be done for long periods such as several days to make thesurface smooth on the round agglomerates. If the starting agglomeratesare not round, they can be made smooth but not round by rolling.Irregularly shaped agglomerates, although having a smooth surface, canjam, obstruct or significantly increase the injection force on a syringeneedle when injected into tissue.

[0045] The agglomerated spherical particles can also be washed free ofsmall particles by using an inclined rotation mill. This can be done byplacing the agglomerates in the mill with purified water and rolled fora sufficient time, such as one hour. The supernate is then poured offand more purified water is added. The process is repeated until thesupernate is relatively clear after a rotating cycle, and usually takesabout three or four operations.

[0046] The methods described above are suitable for any ceramicmaterials which may be employed.

[0047] A smooth surface on the individual round, spherical particles isimportant to reduce and minimize surface porosity. Surface smoothnesscan be improved by finishing operations known in the art, such assurface milling and the like. It is preferred that such smoothingoperations be capable of minimizing surface irregularities on theindividual particles so that the surface appears similar to that of asmooth round bead when viewed under a microscope at 40× magnification.This is apparent from FIG. 1, which is a photomicrograph of calciumhydroxyapatite particles having a particle size distribution of 38 to 63microns. The smooth, round substantially spherical and non-poroussurface is readily evident.

[0048] The ceramic particles are preferably smooth, hard, roundedparticles, having a density on the order of about 75 to 100%, andpreferably about 95 to 100% of the theoretical density of desiredceramic material, e.g., calcium hydroxyapatite. The finishing operationscan also minimize the surface porosity of the calcium hydroxyapatiteparticles to less than about 30%, and preferably less than about 10%.This is preferred, because by minimizing surface porosity, particleswith smooth surfaces can be obtained, thereby eliminating jagged,irregular surfaces and maximizing the ability of the smooth, roundparticles to flow easily in contact with each other.

[0049] Although this invention is described in terms of calciumhydroxyapatite, other suitable materials useful herein include, but arenot limited to, calcium phosphate-based materials, alumina-basedmaterials and the like. Examples include, but are not limited to,tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate,octacalcium phosphate, calcium fluorapatite, calcium carbonate apatite,and combinations thereof. Other equivalent calcium based compositionscan also be used such as calcium carbonate, and the like.

[0050] As noted, the individual ceramic particles used in the presentinvention have a generally smooth, round, preferably spherical shape, incontrast to particles with more textured porous surfaces or openings,and having jagged, irregular shapes or shapes with straight edges. Thesmooth round shape enables the ceramic particles to be more easilyextruded and to flow with reduced friction from a syringe into thetissue site where soft tissue augmentation is desired. Once at thetissue site, the ceramic particles provide a matrix or scaffolding forautogenous tissue growth.

[0051] As mentioned above, particle sizes in the range of about 35 to150 microns are optimal to minimize the possibility of particlemigration by phagocytosis and to facilitate injectability. Phagocytosisoccurs where smaller particles on the order of 15 microns or less becomeengulfed by the cells and removed by the lymphatic system from the sitewhere the augmentation material has been introduced into the tissues,generally by injection.

[0052] At the lower end, particles greater than 15 microns and typically35 microns or above are too large to be phagocytosized, and can beeasily separated by known sizing techniques. Thus, it is relativelysimple to produce the narrow or equivalent particle size ranges that aremost desirable for use in this invention.

[0053] It is also desirable to use a narrow or equivalent particle sizerange of ceramic particles due to the fact that a distribution of suchsmooth, round, substantially spherical particles reduces friction, andfacilitates the ease of injecting the particles by needle from a syringeinto the skin tissue at the desired augmentation site. This is incontrast to the use of the more porous, textured, irregularly shapedparticles which tend to increase the frictional forces, and are muchmore difficult to deliver by injection.

[0054] As discussed above, the particle size distribution, or range ofparticle sizes of the ceramic material within the overall range of 35 to150 microns is preferably minimized to a more narrow or equivalentparticle size range. This maximizes the intraparticle void volume, orinterstitial volume, into which autogenous tissue growth, stimulated bythe presence of the augmentation material, can occur. A greaterinterstitial volume exists between particles that are equivalent insize, compared with particles having a variable size distribution. Inthe context of this invention, the interstitial volume is the void spaceexisting between particles of the augmentation material that are closeto or in contact with each other.

[0055] For example, in crystalline lattice structures such as facecentered cubic, body centered cubic and simple cubic, the percentage ofinterstitial void space, known as the atomic packing factor, is 26%,33%, and 48%, respectively. This is independent of the diameter of theatom or in this case, the particle. Since the ceramic particles neverpack as tightly as the atoms in a crystalline lattice structure, thevoid volume would be even greater, thereby maximizing the growth ofautogenous tissue.

[0056] To extend the analogy of the crystalline structure a stepfurther, the interstitial opening defines the maximum size that aparticle can fit into a normally occurring void space in the structure.The largest interstitial space is about 0.4 times the size of the meanceramic particle in the particle size distribution.

[0057] Thus, if the particle size distribution is about 35 to 65microns, the mean particle size would be 50 microns. The largestinterstitial space would be 50×0.4=20 microns. Since no 20 micron sizeparticles exist in the distribution, packing would be minimized.Similarly, with a particle size distribution of 75 to 125 microns, themean particle size is 100 microns, and the largest interstitial spacewould be 100×0.4=40 microns. Since no 40 micron particles exist in thedistribution, packing would also be minimized. Therefore, if the ceramicparticles are restricted to a narrow particle size range or equivalentsize distribution, there will be a maximizing of the void volume intowhich the is autogenous tissue can grow.

[0058] Other suitable particle size distribution ranges include 35 to 40microns, 62 to 74 microns and 125 to 149 microns, however, any othercorrespondingly narrow ranges can also be used.

[0059] In contrast, where there is a wide particle size distribution,there is a greater tendency for the particles to become densely packedsince the smaller particles tend to group or migrate into the spacesbetween the larger particles. This results in less interstitial spaceavailable between the particles for the autogenous tissue such asfibroblasts and chondroblasts to infiltrate and grow.

[0060] The tissue growth where the augmentation material has a wideparticle size distribution is denser and harder, because of the packingeffect which occurs between the large and small particles. In contrast,the use of particles equivalent in size, or having a narrow particlesize range of uniformly distributed particles increases theintraparticle void volume. This enables a maximum amount of autogenousor three dimensional randomly oriented non-scar soft tissue in growth toinfiltrate the space or interstices between the particles. The moreinterstitial space that is available makes it more likely that thesubsequent autogenous tissue growth stimulated by the presence of theaugmentation material into the matrix or scaffolding provided by theaugmentation material will closely resemble the original tissue in theimmediate vicinity or locus of augmentation.

[0061] The process of soft tissue augmentation can occur by injecting orimplanting the biocompatible augmentation material comprising thedesired particle sizes of the desired ceramic material into the tissueat the desired augmentation site to form a bleb or blister. Thesubsequent autogenous tissue growth into the matrix provided by theaugmentation material will most closely resemble the surrounding tissuein texture and properties. This is in contrast to that which occursusing known state-of the-art procedures, where foreign body response isknown to occur, typically with Teflon® augmentation where granulomashave been known to form.

[0062] Foreign body response is the body reaction to a foreign material.A typical foreign body tissue response is the appearance ofpolymorphonuclear leukocytes near the material followed by macrophages.If the material is nonbioreactive, such as silicone, only a thincollagenous encapsulation tissue forms. If the material is an irritant,inflammation will occur and this will ultimately result in granulationtissue formation. In the case of ceramic materials such as calciumhydroxyapatite, there is excellent biocompatibility resulting in tissuecell growth directly on the surface of the particles with a minimum of,or substantially no encapsulation.

[0063] Autogenous tissue is defined herein as any tissue at a specificdefined location in the body, whose growth is stimulated by the presenceof the matrix of the biocompatible augmentation material at the sitewhere soft tissue augmentation is desired. Such autogenous tissue fromaugmentation in the area of the urethral sphincter would resembleexisting tissue in the urethral sphincter. Autogenous tissue fromaugmentation in the larynx would resemble existing tissue in the glottiswhere the vocal apparatus of the larynx is located. Autogenous tissuefrom breast augmentation would resemble existing tissue in themammaries, and so on. Autogenous tissue in the case of intradermalinjections would resemble the dermis. In a similar manner, theaugmentation material, by providing a three dimensional lattice can beused in surgical incisions or trauma to avoid linear, layeredcontractile scar formation.

[0064] As discussed above, the calcium hydroxyapatite particles used asthe augmentation material are biocompatible and substantiallynon-resorbable. Thus, the soft tissue augmentation procedure ispermanent. Moreover, the use of calcium hydroxyapatite does not requirethe strict rigorous precautions that are necessary when using otheraugmentation materials such as collagen which need refrigeration forstorage, shipping and antigenicity testing.

[0065] The rounded, spherical smooth calcium hydroxyapatite particlesenhance the biocompatibility to the autogenous tissue response into theparticle matrix and substantially eliminates the potential forcalcification. Jagged or irregular particles can irritate tissue and cancause calcification. In addition, surface porosity on the order of about30 volume % or greater can also cause calcification because of therelative stability of the pores in the particles. Smooth round,substantially non-porous particles maintain movement in the tissue.Thus, the autogenous tissue grown in the particle matrix where movementis maintained, does not calcify. In contrast, the porous sections of theindividual particles are stationary relative to the particle, thustissue infiltration into the pores is not subject to movement andcalcification can occur.

[0066] The particulate ceramic material can be suspended in abiocompatible, resorbable lubricant, such as a polysaccharide gel toimprove the delivery of the augmentation material by injection to thetissue site where augmentation is desired. Suitable polysaccharides willbe readily apparent to one skilled in the art. Polysaccharides that maybe utilized in the present invention include, for example, any suitablepolysaccharide within the following classes of polysaccharides:celluloses/starch, chitin and chitosan, hyaluronic acid, hydrophobemodified systems, alginates, carrageenans, agar, agarose, intramolecularcomplexes, oligosaccharide and macrocyclic systems. Examples ofpolysaccharides grouped into four basic categories include: 1. nonionicpolysaccharides, including cellulose derivatives, starch, guar, chitin,agarose and dextron; 2. anionic polysaccharides including cellulosederivatives starch derivatives, carrageenan, alginic acid, carboxymethylchitin/chitosan, hyaluronic acid and xanthan; 3. cationicpolysaccharides including cellulose derivatives, starch derivatives guarderivatives, chitosan and chitosan derivatives (including chitosanlactate); and 4. hydrophobe modified polysaccharides including cellulosederivatives and alpha-emulsan. Preferred polysaccharides for use in thepresent invention include, for example, agar methylcellulose,hydroxypropyl methylcellulose, ethylcellulose, microcrystallinecellulose, oxidized cellulose, chitin, chitosan, alginic acid, sodiumalginate, and xanthan gum.

[0067] The cellulose polysaccharide gels are particularly advantageousbecause of what can be referred to as their viscoelasticcharacteristics. Among these characteristics is that of shear thinning.That is, the cellulose polysaccharide gels will flow more readily asforces are applied thereto. This facilitates the ease of mixing when thesolid granulate is added to the gel. The shear thinning also permits aneasier delivery of the viscous material than would otherwise be thecase. Another characteristic of the material is that it is elastic inthat it tends to recover its initial shape after being deformed. This ishighly significant because the elastic nature of the gel allows for thegel to suspend the augmentation material substantially indefinitelytherefore achieving a substantially indefinite shelf life. Materials ofrelatively high density may be suspended by this gel. For example,calcium hydroxylapatite granulate, spherically shaped with diametersranging from 75 to 125 micrometers, and with a density of 3.10 g/cc canbe indefinitely suspended in a gel with a composition of 14.53 partsglycerin, 82.32 parts water, and 3.15 parts NaCMC.

[0068] The elastic characteristics of the gel in accordance with thepresent invention are further advantageous because the tissueaugmentation material and the cellulose polysaccharide gel can besubjected to mixing to suspend the tissue augmentation material in thegel using conventional mixing apparatus without adverse impact on thegel carrier. That is, the gel carrier will not break down or lose itselastic properties. These processes are enhanced by the rate of recoveryof gel elastic properties which occurs in a matter of seconds once thehydrated gel has been formed. This rapid recovery of shape due to theelasticity is also highly significant for placement and retention of thematerial when implanted into living tissue. The recovery of a moreviscous characteristic, once the force of injection is removed, assistsin the retention in place of the material, minimizing extravasation.

[0069] Any suitable solvent for the cellulose polysaccharide gel may beutilized in the present invention. For example, the gel may be anaqueous cellulose polysaccharide gel. Alternatively, the solvent may bean aqueous alcohol, including for example, glycerol, isopropyl alcohol,ethanol, and ethylene glycol, or mixtures of these. Other suitablesolvents for the gel carrier will be apparent to one skilled in the art.Surfactants, stabilizers, pH buffers, and other additives may also beuseful, as would be obvious to one skilled in the art. Pharmaceuticallyactive agents, such as growth factors, antibiotics, analgesics, etc.could also be usefully incorporated and would be apparent to one skilledin the art.

[0070] In addition, while the present invention has been describedherein with respect to a ceramic tissue augmentation material, thecellulose polysaccharide gel carrier of the present invention may alsobe utilized as a carrier for other tissue augmentation material. Forexample, the cellulose polysaccharide gel carrier of the presentinvention may be utilized as a carrier for non-ceramic tissueaugmentation material such as, glass, polymethyhnethacrylate, silicone,titanium and other metals, etc. Other suitable non-ceramic tissueaugmentation material that may be suspended using the carrier of thepresent invention will be apparent to one skilled in the art.

[0071] The formulation of the gel will depend on a number of factors,including: 1) the molecular weight, degree of substitution, and otherproperties of the polysaccharide, 2) the solvent system employed, and 3)final properties required for the particular application of thematerial. In general, the ratio of cellulose polysaccharide to solventcan vary from about 0.5 to 10: 95.5 to 90. For example, in an 85:15water:glycerin mixture, the ratio is preferably about 1.5 to 5: 98.5 to95, and most preferably about 2.5 to 3.5: 97.5 to 96.5, respectively.

[0072] Preferably, the gel comprises water, glycerin and sodiumcarboxymethylcellulose. The gel enables the ceramic particles to remainin suspension without settling for an indefinite period of time untilused, more specifically, at least about 6 months. Other suitablelubricant compositions known in the art can also be employed.

[0073] In general, the ratio of water (or other solvent, e.g. saline,Ringer's solution, etc.) to glycerin in the gel can vary from about 10to 100:90 to 0, preferably about 20 to 90:80 to 10, and most preferablyabout 85:15, respectively.

[0074] The viscosity of the gel can vary from about 20,000 to about350,000 centipoise, preferably about 150,000 to about 250,000centipoise, and more preferably from greater than 200,000 to about250,000 centipoise as measured with a Brookfield Viscometer with RU#7spindle at 16 revolutions per minute (rpm) at 25° C. It has been foundthat with gel viscosities below about 20,000 centipoise the particlesmay not remain in suspension, and with gel viscosities above about350,000 centipoise, the gel may become too viscous for convenientmixing.

[0075] In a preferred embodiment of the invention wherein thepolysaccharide is sodium carboxymethylcellulose, the sodiumcarboxymethylcellulose included in the gel has a high viscosity. Morespecifically, the sodium carboxymethylcellulose preferably has aviscosity of about 1000 to 4000 centipoise, preferably about 2000 to3000 centipoise, in a 1% aqueous solution per a procedure given inHercules/Agualon Division Brochure 250-10F EV. 7-95 2M, “SodiumCarboxymethylcellulose Physical and Chemical Properties,” pp. 26-27. Thecarboxymethylcellulose content can vary from about 0.25 to 5 weight %,preferably 2.50 to 3.50% of the combined (85 parts) water and (15 parts)glycerin in the gel.

[0076] The cellulose polysaccharide gel carrier of the present inventionhas been discussed in connection with the preferred sodiumcarboxymethylcellulose gel carrier. However, as discussed above, anysuitable polysaccharide gel may be utilized for the carrier inaccordance with the present invention, provided it suspends the tissueaugmentation material homogeneously therein for a substantiallyindefinite period of time and possesses the shear thinning and elasticproperties described above. More specifically, the polysaccharide gelcarrier preferably has the following shear thinning and elasticproperties: 1) a viscosity of between 1 and 5 million centipoise whenstressed with a shear of 200 Pascals and a viscosity of 300,000 to 1million cps when stressed with a shear of 500 Pa; 2) an elastic modulus,under a 100 Pa. maximum force measured at 1 hertz, of 50 to 1000 Pa.; 3)a ratio of viscous modulus to elastic modulus of 0.2 to 1.0, whenmeasured under a 100 Pa. maximum force at 1 hertz; 4) a recovery ofdeformation of 5 to 75% after being subjected to a deformation force of100 Pa for 120 seconds; and, 5) a majority of the recovery of thedeformation in (4) should occur in 2 to 10 seconds. The measurementsdescribed above can be conducted with a controlled stress rheometer,e.g. a Häake RS100 with a 2 cm. parallel plate, operating in stressramp, oscillatory, and creep/recovery modes. The actual values of theshear thinning and elastic properties described above will depend on theintended application and properties (e.g. size, density, etc.) of adispersed particulate.

[0077] In the tissue augmentation material and method of the presentinvention, other polysaccharides can also be included or used separatelysuch as cellulose, agar methylcellulose, hydroxypropyl methylcellulose,ethylcellulose, microcrystalline cellulose, oxidized cellulose, chitin,chitosan, alginic acid, sodium alginate, xanthan gum and otherequivalent materials.

[0078] Unexpectedly, formulating the augmentation particles of thepresent invention, particularly the calcium hydroxyapatite with sodiumcarboxymethylcellulose, provides a change in the surface morphology ofthe particles which is believed to enhance the physical andbiocompatible properties of the material.

[0079] The glycerin in the preferred formulation provides severaladvantages. First, the composition is more lubricious when glycerin ispresent. Second, for a given level of polysaccharide gel former, theviscosity is substantially enhanced with some glycerin relative to apure aqueous gel. Third, the presence of the glycerin minimizes moistureloss of the gel by dessication.

[0080] The gel is prepared by mixing the gel components at ambientconditions until all components are in solution. It is preferable to iscombine the glycerin and NaCMC components together first until athoroughly mixed solution is obtained. The glycerin/NaCMC solution isthen mixed together with the water until all components are in solutionto form the gel. After the gel components have been thoroughly mixed,the gel is allowed to set for a minimum of 4 hours, after whichviscosity readings are taken to ensure that the gel has the desiredviscosity.

[0081] While any lubricant or carrier can be employed, it has been foundthat certain materials, e.g., polysorbate surfactants, pectin,chondroitin sulfate and gelatin, are not able to suspend the ceramicparticles for an indefinite amount of time and allow further processingor be as easy to inject in the same manner as the preferred sodiumcarboxymethylcellulose. Thus, the sodium carboxymethylcellulosematerials are preferred.

[0082] The preferred polysaccharide gel is biocompatible and able tomaintain the particles of ceramic material in what amounts to asubstantially permanent state of suspension so that the ceramicparticulate/gel composition comprising the augmentation material doesnot require mixing before use. As already noted, the lubricious natureof the polysaccharide gel reduces the frictional forces generated bytransferring the augmentation material from a syringe by injection intothe tissue site.

[0083] In addition, the polysaccharides do not generate an antigenicresponse as do products containing amino acids. The polysaccharide gelis readily sterilizable and stable at ambient conditions and does notneed refrigeration for storage and shipment, in contrast to systems usedwith collagen containing materials.

[0084] Sterilization is ordinarily accomplished by autoclaving attemperatures on the order of about 115° C. to 130° C., preferably about120° C. to 125° for about 30 minutes to 1 hour. Gamma radiation isunsuitable for sterilization since it tends to destroy the gel. It hasalso been found that sterilization generally results in reduction of itsviscosity. However, this does not adversely affect the suspension andtherefore the extrusion force of the augmentation material through asyringe, nor does it affect the ability of the gel to hold the calciumhydroxyapatite particles in suspension, as long as the prescribedviscosity ranges for the gel are maintained.

[0085] After injection of the augmentation material into the tissue, thepolysaccharide gel is harmlessly resorbed by the tissue, leaving thenonresorbable calcium hydroxyapatite matrix in place in the particulararea or bolus, where it has been found to remain without migrating toother areas of the body. It generally takes an average of about 2 weeksfor the polysaccharide to completely resorb.

[0086]FIG. 2 shows a histological section of rabbit 10 tissue at 50×magnification which has been infiltrated with autogenous threedimensional, randomly oriented, non-scarring soft muscle tissue as aresult of an injection of calcium hydroxyapatite particles having auniform particle size distribution of 38 to 63 microns. Thephotomicrograph shows growth after 12 weeks. The histological sectionalso demonstrates the biocompatibility of the calcium hydroxyapatite asthe cells grow on the surface of the particles with minimal orsubstantially no foreign body response.

[0087] It has been found that the amount of calcium hydroxyapatiteparticles in the augmentation material can vary from about 15% to 50% byvolume, and preferably about 25% to 47.5% and most preferably about 35%to 45% by volume of the total augmentation material, comprising the geland the ceramic particles.

[0088] Preparations having above 50 volume % ceramic particles becomeviscous and care should be taken as to the selection of injectionapparatus. As a lower limit the augmentation material of this inventionshould obviously contain a sufficient volume of ceramic particles toprovide an effective base for autogenous tissue growth. For mostapplications this is at least 15 volume %. By maintaining a volume % ofabout 35 to 45%, a correction factor of about 1:1 can be achieved, thatis, the volume of autogenous tissue growth is roughly equivalent to thevolume of particles introduced and shrinkage or expansion at the site ofthe soft tissue augmentation does not generally occur.

[0089] Also, within these parameters, the augmentation material caneasily be injected through an 18 gauge or smaller syringe intradermallyor subcutaneously. Because of the reduced frictional forces necessary todeliver the biocompatible augmentation material by injection to thedesired tissue site, the size of the syringe used to transfer or injectthe biocompatible augmentation material can be significantly reduced.This substantially eliminates the possibility of creating a needle trailthrough which leakage of the augmentation material from the injectionsite can occur after withdrawing the injection needle. Thus, thesyringes used to inject the augmentation material can have reducedopenings of less than 1,000 microns in diameter to a minimum of about178 microns or less.

[0090] For example, an 18 gauge syringe having a diameter of about 838microns, or a 20 gauge syringe having a diameter of about 584 microns,or a 22 gauge syringe having a diameter of about 406 microns, and even a28 gauge syringe having a diameter of about 178 microns can be used,depending on the tissue site where augmentation is needed.

[0091] The lubricious suspension of augmentation material is prepared bysimply mixing the desired amount of ceramic particles with thelubricious gel until a uniform, homogeneous suspension is reached. Theconsistency of the ceramic particles suspended in the lubricious gel iscomparable to strawberry preserves, wherein the seeds and other solidparts of the strawberry, for all practical purposes, are comparable tothe ceramic particles and remain substantially permanently suspended inthe jelly preserve matrix.

[0092] The suspension of ceramic material in the lubricious gel is sostable, that centrifugation at forces on the order of 500 g's, that is,500 times the force of gravity generally do not affect the stability ofthe suspension or cause it to settle out. The tendency, if any, forparticles to settle out over a period of time would appear more likelyto occur with the larger particle sizes on the order of 125 microns orlarger. Thus, remixing the augmentation material at the time ofinjection or implantation is ordinarily not necessary. In addition, thepolysaccharide gel lubricates the suspended ceramic particles so thatthe injection force on the syringe can be minimized when injecting theaugmentation material.

[0093] Tissue augmentation material in accordance with the presentinvention is particularly advantageous in the treatment of osteoporosisor related pathologies in, for example, the femur, or osseous defectsdue to trauma or surgical incision. The advantages of this material inthese applications include biocompatibility, ease of application, and asuperior result to other materials currently employed.

[0094] Specifically, because the material can be injected through finecatheters and needles, small incision sites such as less than a 4.5 mmhole in the bone site may be used, resulting in minimizing the immediateloss of bone trabeculae—the opposite of the intended longer term result.Because of the smaller needle required for using tissue augmentationmaterial in accordance with the present invention, the hole diametercould be greatly reduced and the depth could also be greatly reduced.

[0095] Particles are held together in the present invention for sometime by the gel carrier, even in a liquid environment. In an osseoussite, the gel would provide a means of “fixing” the particles for aperiod of time.

[0096] Furthermore, because the particulate is relatively small, it isdistributed more widely in the site of interest via injection. Theviscosity of the gel carrier could be tailored to produce either a“thin, runny” consistency media or a “thick, robust” consistency, asdesired. This could be done by modifying the content of the othercomponents of the composition including, for example, glycerin andsodium carboxymethylcellulose.

[0097] The particle size of the ceramic particulate in the tissueaugmentation material could be reduced for this application. That is,material which could be used would be a 37-63 μm CaHA particulate. Themain advantage of a larger size range of particle sizes in soft tissueis to ensure a lack of migration due to cellular mechanisms that couldtransport the particulate to distant organ sites. The chance of thisoccurring, however, would be greatly reduced for particulate contained,for example, within a trabecular bone cavity. Also, the fact that CaHAis known to bond to bone further reduces concern of migration.

[0098] Also, it has been discovered that tissue augmentation material inaccordance with the present invention can be the basis for a uniquematerial useful in implant applications. Specifically, it has beendiscovered that if tissue augmentation material in accordance with theinvention is allowed to dry by exposure to air, it developed somesurprising properties. If extruded from a syringe, either directly orthrough a needle or catheter, a “string” of particles with surprisingcohesion and flexibility would result after exposure to air. It wasapparent that the material was substantially dehydrated and it ispossible to form the material in various shapes or into sheets, asdesired. The material may be molded and shaped like clay or carved intoshape with appropriate instruments to prepare a preform forimplantation. The advantages of this material include cohesion,moldability, and the high concentration of particulate per unit volume.

[0099] The following examples show specific embodiments of theinvention. All parts and percentages are by weight unless otherwisenoted.

EXAMPLES Example 1

[0100] Preparation of The Gel

[0101] A mixture of 15% glycerin, 85% water, (based on the combinedweight of the water and glycerin) and 3.25% NaCMC (again based on thetotal of the liquid components) is prepared in the following manner:

[0102] 9.303 g of glycerin and 2.016 g of NaCMC are combined in avessel. The mixture is then slowly added to 52.718 g of agitating waterin a container large enough for batch size and allowed to mix, utilizingan electric mixer, for 30 minutes at a medium speed. The gel is allowedto set for a minimum of four hours.

Example 2

[0103] Preparation of the Augmentation Composition

[0104] Aqueous glycerin/NaCMC gel (44.04 g, prepared in Example 1) areplaced in a mixing container large enough for batch size. Smooth,rounded substantially spherical CaHA particles (55.99 g) having auniform particle size of 75 to 125 microns are thoroughly blended,utilizing an electric mixer, for five minutes at a low speed until allthe particles are homogeneously distributed in a uniform suspension inthe gel. The blended material is packaged in 3 cc polysulfone cartridgesand sterilized in an autoclave for 60 minutes at 121° C.

Example 3

[0105] Properties of Augmentation Composition

[0106] The gel as prepared in Example 1, and the augmentation medium asprepared in Example 2 are examined by means of a parallel platerheometer (Häake RS 100). Testing includes the measurement ofrheological properties as a function of applied stress (stress ramp),deformation at constant stress followed by recovery at 0 stress(creep/recovery), and the measurement of the complex modulus using anoscillating stress within the viscoelastic limit of the composition(frequency sweep). Outcomes demonstrate that the behavior of the gel andaugmentation composition, both before and after sterilization, is thesame. For example, this is demonstrated in FIG. 3, which shows theviscosity of the gel and augmentation material before and aftersterilization as a function of applied stress from 10 to 1000 Pascals.The shape of the curves are similar and demonstrate the shear thinningcharacteristic of this material. Other measured values are given in thefollowing table. The viscosity is determined at 500 Pa in a stress rampmeasurement. The elastic modulus is determined under an oscillatingforce of 100 Pa at 1 hertz. The ratio of the inelastic modulus toelastic modulus, tan δ, is determined under an oscillating force of 100Pa at 1 hertz. The maximum deflection, δ max′ is determined after 120seconds of a constant 100 Pa applied stress. The % Recovery isdetermined after a relaxation of 200 seconds following 120 seconds of aconstant 100 Pa applied stress. TABLE 1 Rheological results of gel andaugmentation materials taken on a Häake RS100 control stress rheometerusing 2 cm. parallel plates. As Prepared Sterilized As PreparedAugmentation Augmentation Gel Composition Composition Viscosity (Cp) @603,000 4,610,000 4,340,000 500 Pa stress Elastic Modulus 408 2520 2684(100 Pa @ 1 Hz) tan δ (100 Pa @ 0.461 0.453 0.429 1 Hz) γ max 2.2270.367 0.345 % Recovery 44.99 45.50 46.96

Example 4

[0107] Preparation of the Gel

[0108] A mixture of 25% glycerin, 75% water, and 2.25% NaCMC (based onthe combined weight of the water and glycerin) is prepared in thefollowing manner:

[0109] 87.90 g of glycerin and 7.91 g of NaCMC are combined in a vessellarge enough to mix the total mass. The mixture is then slowly added to263.71 g of agitating water in a container large enough for batch sizeand allowed to mix, utilizing an electric mixer, for 30 minutes at amedium speed. The gel is allowed to set for a minimum of four hours.

Example 5

[0110] Preparation of the Augmentation Composition

[0111] Aqueous glycerin/NaCMC gel (38.52 g, prepared in Example 1) areplaced in a mixing container large enough for batch size, Smooth,rounded substantially spherical CaHA particles (74.86 g) having auniform particle size of 37 to 63 microns are thoroughly blended,utilizing an electric mixer, for five minutes at a low speed until allthe particles are homogeneously distributed in a uniform suspension inthe gel.

Example 6

[0112] In most instances it takes relatively little force to inject orextrude the augmentation composition, comprising the polysaccharidegel/particulate calcium hydroxyapatite suspension, into the air sincethere is relatively little resistance. However, greater forces werenecessary to inject the augmentation composition into tissue, and thisforce is significantly influenced by the shape of the particulatematerial. This was exemplified by preparing sterilized suspensions ofpolysaccharide gel made of 75% water, 25% glycerin, and 2.25% sodiumcarboxymethylcellulose (based on the combined weight of the water andglycerin) with various volume percents of calcium hydroxyapatiteparticles having different shapes, following the procedure of Example 2.The thus prepared suspensions were placed in standard 3 cubic centimetersyringes. The force applied to the plunger to extrude the polysaccharidegel/particulate suspension at a rate of one inch per minute through an18 gauge needle was then measured. The force was also measured with theneedle inserted into turkey gizzard tissue as an analogy as it would beused clinically. The spray dried particles of calcium hydroxyapatite,regardless of their shape, had a smooth, uniform appearance undermicroscopic examination at 40× magnification. The particles wereuniformly distributed within the range of particle sizes. The resultsare tabulated in Table 2, which follows: TABLE 2 Calcium HydroxyapatiteParticles in the Gel Size, Volume, Force, lbs Microns Particle Shape %Solids Air Tissue 38 to 63 Spherical/Smooth 35 4.5 6.0 38 to 63Spherical/Smooth 40 5.9 7.2 38 to 63 Irregular 40 8.0* 9.6* 74 to 100Irregular/Smooth 37 5.5 >30 74 to 100 Irregular/Smooth 41 >30 >30 74 to100 Spherical/Smooth 42 4.8 5.5

[0113] *Average Inconsistent results due to complete obstruction ofneedle that sporadically occurred during the tests, requiringreplacement of needle.

[0114] This data correlated with animal experimentation where it was notpossible to inject irregular particles into tissue even when the percentsolids were reduced below 25 volume % or a 16 gauge needle was used.

Example 7

[0115] Sterilized samples of polysaccharide gel/particulate calciumhydroxyapatite suspensions were prepared using a series of designatedparticle size ranges. The distribution of particles was uniform withineach range of particle sizes. The particles were smooth, round calciumhydroxyapatite, and the gel had the same constituency as Example 1. Thecalcium hydroxyapatite particles occupied 36 volume % of the suspension.The extrusion force into the air for each suspension containing eachdesignated range of particle sizes was measured using a standard 3 cubiccentimeter syringe in the same manner as in Example 6. The results aretabulated in Table 3, which follows, and demonstrate that littledifference in the extrusion force occurs as the particle size increases,as long as the particle sizes are uniform and maintained in a narrowdistribution range. TABLE 3 Size Distribution, Extrusion Force, micronslbs  40-60 2.3  62-74 2.0  40-74 2.6  82-100 2.3 100-125 2.2 125-149 2.4100-149 2.4

Example 8

[0116] Sodium carboxymethylcellulose, water and glycerin in variousweight percents were formulated into four different gels following theprocedure of Example 1, except for the use of different proportions.Each gel was then blended with about 40 volume % calcium hydroxyapatiteparticles having a distribution of 38 to 63 microns. The gel/particleblends were then placed in standard 3 cubic centimeter syringes fittedwith 18 gauge, 20 gauge and 22 gauge needles. The extrusion force of theblend into the air was measured in the same manner as in Example 3. Theresults appear below in Table 4. TABLE 4 Weight % Force, lbs % NaCMC*Glycerin Water 18 gauge 20 gauge 22 gauge 1.0 60 40 3.6 6.4 7.7 1.5 5050 4.0 5.8 8.2 2.0 30 70 4.1 6.3 7.7 2.0 40 60 4.8 7.0 9.2

Example 9

[0117] Preparation of the Augmentation Composition

[0118] Using Polystyrene Microbeads

[0119] A gel consisting of 4.93% glycerin, 93.60% water, and 1.48% NaCMCwas prepared by methods described in Example 1. Spherical polystyrenebeads (12.79 g), having a particle size range of 100 to 500 microns arethoroughly blended, utilizing an electric planetary mixer, for fiveminutes at a low speed until all the particles are homogeneouslydistributed in a uniform suspension in 28.43 grams of gel. Thepolystyrene beads have a density of 1.07 g/cc as measured by heliumpycnometry. The blended material is packaged in 10 cc polypropylenesyringe cartridges and sterilized in an autoclave for 60 minutes at 121°C. The polystyrene beads remained homogeneously distributed within thegel carrier. Rheologic properties were measured as described in Example3. The viscosity is determined at 100 Pa in a stress ramp measurement.The elastic modulus is determined under an oscillating force of 20 Pa at1 hertz. The ratio of the inelastic modulus to elastic modulus, tan δ,is determined under an oscillating force of 20 Pa at 1 hertz. Themaximum deflection, γ max′ is determined after 120 seconds of a constant10 Pa applied stress. The % Recovery is determined after a relaxation of200 seconds following 120 seconds of a constant 10 Pa applied stress.Results are shown in Table 5. TABLE 5 Rheological results of gel andpolystyrene augmentation material taken using a Häake RS100 controlstress rheometer using 2 cm. parallel plates. As Prepared Sterilized AsPrepared Augmentation Augmentation Gel Composition Composition Viscosity(Cp) @ 2,050 47,900 9,630 100 Pa stress Elastic Modulus 11 31 16 (20 Pa@ 1 Hz) tan δ (20 Pa @ 1.348 1.320 2.067 1 Hz) γ max. (@ 10 Pa.) 27.4065.717 47.873 % Recovery 22.4 23.4 1.6

Example 10

[0120] Preparation of the Augmentation Composition

[0121] Using Polymethylmethacrylate Microbeads

[0122] A gel consisting of 9.80% glycerin, 88.24% water, and 1.96% NaCMCwas prepared by methods described in Example 1. Sphericalpolymethylmethacrylate beads (12.78 g), having a uniform particle sizeof 100 to 180 microns are thoroughly blended, utilizing an electricplanetary mixer, for five minutes at a low speed until all the particlesare homogeneously distributed in a uniform suspension in 28.84 grams ofgel. The polymethylmethacrylate beads have a density of 1.21 g/cc asmeasured by helium pycnometry. The blended material is packaged in 10 ccpolypropylene syringe cartridges and sterilized in an autoclave for 60minutes at 121° C. The polymethylmethacrylate beads remain homogeneouslydistributed within the gel carrier. Rheologic properties were measuredas described in Example 6. The viscosity is determined at 100 Pa in astress ramp measurement. The elastic modulus is determined under anoscillating force of 20 Pa at 1 hertz. The ratio of the inelasticmodulus to elastic modulus, tan δ, is determined under an oscillatingforce of Pa at 1 hertz. The maximum deflection, γ max′ is determinedafter 120 seconds of a constant 20 Pa applied stress. The % Recovery isdetermined after a relaxation of 200 seconds following 120 seconds of aconstant 20 Pa applied stress. Results are shown in Table 3. TABLE 6Rheological results of gel and polymethylmethacrylate augmentationmaterial taken using a Häake RS100 control stress rheometer using 2 cm.parallel plates. As Prepared Sterilized As Prepared AugmentationAugmentation Gel Composition Composition Viscosity (Cp) @ 58,700 482,00022,200 100 Pa stress Elastic Modulus 58 212 42 (20 Pa @ 1 Hz) Tan δ (20Pa @ 0.785 0.705 1.934 1 Hz) γ max 2.895 1.111 0.211 % Recovery 53.148.2 20.9

Example 11

[0123] Preparation of the Augmentation Composition

[0124] Using Glass Microbeads

[0125] A gel consisting of 14.56% glycerin, 82.52% water, and 2.91%NaCMC was prepared by methods described in Example 1. Spherical glassbeads (30.42 g), having a uniform particle size of 30 to 90 microns arethoroughly blended, utilizing an electric planetary mixer, for fiveminutes at a low speed until all the particles are homogeneouslydistributed in a uniform suspension in 29.27 grams of gel. The glassbeads have a density of 2.54 g/cc as measured by helium pycnometry. Theblended material is packaged in 10 cc polypropylene syringe cartridgesand sterilized in an autoclave for 60 minutes at 121° C. The glass beadsremain homogeneously distributed within the gel carrier. Rheologicproperties were measured as described in Example 3. The viscosity isdetermined at 500 Pa in a stress ramp measurement. The elastic modulusis determined under an oscillating force of 100 Pa at 1 hertz. The ratioof the inelastic modulus to elastic modulus, tan δ, is determined underan oscillating force of 100 Pa at 1 hertz. The maximum deflection, γmax′ is determined after 120 seconds of a constant 100 Pa appliedstress. The % Recovery is determined after a relaxation of 200 secondsfollowing 120 seconds of a constant 100 Pa applied stress. Results areshown in Table 7. The sterilized augmentation material was filled into 3cc syringe cartridges and extruded through 3.5 inch gauge spinalneedles. The average extrusion force was 14.63 lbs. with a standarddeviation of 0.09 lbs. TABLE 7 Rheological results of gel and glassaugmentation material taken using a Häake RS100 control stress rheometerusing 2 cm. parallel plates. As Prepared Sterilized As PreparedAugmentation Augmentation Gel Composition Composition Viscosity (Cp) @135,000 803,000 569,000 500 Pa stress Elastic Modulus 256 699 570 (100Pa @ 1 Hz) tan δ (100 Pa @ 0.545 0.557 0.692 1 Hz) γ max 4.302 1.1953.259 % Recovery 36.3 37.7 24.7

Example 12

[0126] Preparation of the Augmentation Composition

[0127] Using Stainless Steel Microbeads

[0128] A gel consisting of 4.76% glycerin, 90.48% water, and 4.76% NaCMCwas prepared by methods described in Example 1. The mixing time wasextended from 30 minutes to one hour for this formulation. Sphericalstainless steel beads (95.19 g), having a uniform particle size of 60 to125 microns are thoroughly blended, utilizing an electric planetarymixer, for five minutes at a low speed until all the particles arehomogeneously distributed in a uniform suspension in 28.69 grams of gel.The stainless steel beads have a density of 7.93 g/cc as measured byhelium pycnometry. The blended material is packaged in 10 ccpolypropylene syringe cartridges and sterilized in an autoclave for 60minutes at 121° C. The stainless steel beads remain homogeneouslydistributed within the gel carrier. Rheologic properties were measuredas described in Example 3. The viscosity is determined at 500 Pa in astress ramp measurement. The elastic modulus is determined under anoscillating force of 100 Pa at 1 hertz. The ratio of the inelasticmodulus to elastic modulus, tan 6, is determined under an oscillatingforce of 100 Pa at 1 hertz. The maximum deflection, 7 max′ is determinedafter 120 seconds of a constant 100 Pa applied stress. The % Recovery isdetermined after a relaxation of 200 seconds following 120 seconds of aconstant 100 Pa applied stress. Results are shown in Table 8. Thesterilized augmentation material was filled into 3 cc syringe cartridgesand extruded through 3.5 inch 20 gauge spinal needles. The averageextrusion force was 30.84 lbs with a standard deviation of 0.37 lbs.TABLE 8 Rheological results of gel and stainless steel augmentationmaterial taken on a Häake RS100 control stress rheometer using 2 cm.parallel plates. As Prepared Sterilized As Prepared AugmentationAugmentation Gel Composition Composition Viscosity (cp) @ 8,150,00042,400,000 23,600,000 500 Pa stress Elastic Modulus 1663 8411 5085 (100Pa @ 1 Hz) tan 6 (100 Pa @ 0.335 0.366 0.400 Hz 1) γ max 0.336 0.1100.197 % Recovery 62.8 64.5 54.3

Example 13

[0129] Preparation of the Augmentation Composition

[0130] Using a Xanthan Gum Gel Former

[0131] A gel consisting of 13.8 parts glycerin, and 78.2 parts water,and 8 parts xanthan gum polysaccharide was prepared by methods describedin Example 1. The viscosity of the gel, measured using a BrookfieldRheometer, was 51,250 cps. Calcium hydroxylapatite granulate in a rangeof 75 to 125 microns in diameter are thoroughly blended, utilizing anelectric planetary mixer, for five minutes at a low speed until all theparticles are homogeneously distributed in a uniform suspension in ofgel. The blended material is packaged in polypropylene syringecartridges and sterilized in an autoclave for 60 minutes at 121° C. Thehydroxlyapatite particulate remained homogeneously distributed withinthe gel carrier. Centrifugation of the cartridges in a IEC Clinicalcentrifuge, Model 0M428, at a force of 1016× g for 5 minutes did notresult in a settling of the particulate in the gel carrier. (This resultsuggests that the particulated will not settle even over an extendedperiod of time as the elastic limit of the gel will not be exceeded.)The augmentation material was extruded from the syringe cartridgesthrough 1.5 inch long 18 gauge needles. The force required was 3.90 lbs.

Example 14

[0132] Preparation of the Augmentation Composition

[0133] Using A Xanthan Gum Gel Former and Isopropylacohol

[0134] A gel consisting of 64.4 parts isopropyl alcohol, and 27.6 partswater, and 8 parts xanthan gum polysaccharide was prepared by methodsdescribed in Example 1. The viscosity of the gel, measured using aBrookfield Rheometer, was 37,500 cps. Calcium hydroxylapatite granulatein a range of 75 to 125 microns in diameter are thoroughly blended,utilizing an electric planetary mixer, for five minutes at a low speeduntil all the particles are homogeneously distributed in a uniformsuspension in of gel. The blended material is packaged in polypropylenesyringe cartridges and sterilized in an autoclave for 60 minutes at 121°C. The hydroxylapatite particulate remained homogeneously distributedwithin the gel carrier. Centrifugation of the cartridges in a IECClinical centrifuge, Model 0M428, at a force of 1016× g for 5 minutesdid not result in a settling of the particulate in the gel carrier.(This result suggests that the particulated will not settle even over anextended period of time as the elastic limit of the gel will not beexceeded.) The augmentation material was extruded from the syringecartridges through 1.5 inch long 18 gauge needles. The force requiredwas 7.34 lbs.

Example 15

[0135] The gel is prepared in accordance with Example 1, and theaugmentation medium is prepared in accordance with Example 2. Thepatient is then appropriately anesthetized and a hole (greater indiameter than an 18 gauge needle) is then drilled with an entry point inthe soft cancellous part of the greater trochanter into the neck, headand trochanteric region of the femur. An 18 gauge needle 3.5 inches longis connected to the syringe containing the augmentation media using theLuer lock connection. The augmentation media is then injected throughthe hole in the bone. Sufficient material is injected to serve as ascaffold for bone growth between the particles creating osseousformation and strengthening of the trochanter and the femoral head ofthe femur and thus reducing the risk of fracture.

[0136] Although the present invention has been described in connectionwith preferred embodiments thereof, many other variations andmodifications and other uses will become apparent to those skilled inthe art without departing from the scope of the invention. It ispreferred, therefore, that the present invention not be limited by thespecific disclosure herein, but only by the appended claims.

What is claimed:
 1. A tissue augmentation composition, comprising: abiomaterial for augmenting a desired tissue site; a biocompatible,resorbable, lubricous carrier for homogeneously suspending thebiomaterial both prior to and during the introduction of the compositionto the desired tissue site; and a pharmaceutically active agent disposedin the carrier, wherein the carrier comprises a polysaccharide gelhaving a viscosity between about 20,000 centipoise and about 350,000centipoise.
 2. The tissue augmentation composition of claim 1, whereinthe carrier comprises a polysaccharide gel having a viscosity betweenabout 150,000 centipoise to about 250,000 centipoise.
 3. The tissueaugmentation composition of claim 2, wherein the carrier comprises apolysaccharide gel having a viscosity between about 200,000 centipoiseto about 250,000 centipoise.
 4. The tissue augmentation composition ofclaim 1, wherein the pharmaceutically active agent comprises a growthfactor.
 5. The tissue augmentation composition of claim 1, wherein thepharmaceutically active agent comprises an antibiotic.
 6. The tissueaugmentation composition of claim 1, wherein the pharmaceutically activeagent comprises an analgesic.
 7. The tissue augmentation composition ofclaim 1, further comprising an additive.
 8. The tissue augmentationcomposition of claim 7, wherein the additive comprises at least one of asurfactant, a stabilizer, and a pH buffer.
 9. The tissue augmentationcomposition of claim 1, wherein the biomaterial comprises a materialselected from the group consisting of a ceramic, polymethylmethacrylate,glass, a metal, silicone and mixtures thereof.
 10. The tissueaugmentation composition of claim 9, wherein the metal comprisestitanium.
 11. The tissue augmentation composition of claim 1, whereinthe desired tissue site is a soft tissue site.
 12. The tissueaugmentation composition of claim 1, wherein the composition isimplantable into the human body, and wherein carrier maintains itsviscous and elastic properties after implantation.
 13. The tissueaugmentation composition of claim 1, wherein the desired tissue site isa hard tissue site.
 14. The tissue augmentation composition according toclaim 14, wherein the desired tissue site is an osseous site.
 15. Thetissue augmentation composition according to claim 15, wherein thedesired tissue site is an osseous site in a state of osteoporosis. 16.The tissue augmentation composition according to claim 1, wherein thecarrier maintains its elastic characteristics after the forming of thecomposition.
 17. The tissue augmentation composition of claim 1, whereinthe polysaccharide gel comprises a polysaccharide selected from thegroup consisting of a cellulose polysaccharide, starch, chitin,chitosan, hyaluronic acid, hydrophobe modified polysaccharide, analginate, a carrageenan, agar, agarose, an intramolecular complex of apolysaccharide, an oligosaccharide and a macrocylic polysaccharide. 18.A composition for homogeneously suspending a biomaterial prior andduring introduction of the biomaterial to a desired tissue site, thecomposition comprising: a biocompatible, resorbable, lubricous carrierincluding a polysaccharide gel having a viscosity between about 20,000centipoise and about 350,000 centipoise; and a pharmaceutically activeagent disposed in the carrier.
 19. The composition of claim 18, whereinthe carrier comprises a polysaccharide gel having a viscosity betweenabout 150,000 centipoise to about 250,000 centipoise.
 20. Thecomposition of claim 18, wherein the pharmaceutically active agent isselected from the group consisting of a growth factor, an antibiotic andan alalgesic.
 21. The tissue augmentation composition of claim 18,further comprising an additive.
 22. The composition of claim 18, whereinthe biomaterial comprises a material selected from the group consistingof a ceramic, polymethylmethacrylate, glass, a metal, silicone andmixtures thereof.
 23. The composition of claim 18, wherein the desiredtissue site is a hard tissue site.
 24. The composition of claim 18,wherein the desired tissue site is a soft tissue site.
 25. In abiocompatible composition for augmenting tissue, the compositioncomprising a biomaterial for augmenting tissue and a biocompatible,resorbable, lubricous carrier, the improvement comprising apolysaccharide gel carrier having a viscosity between about 20,000centipoise to about 350,000 centipoise and further including apharmaceutically active agent disposed in the carrier, the carrier alsohomogeneously suspending the biomaterial in the composition prior to andduring the introduction of the composition to a desired tissue site. 26.The composition of claim 26, wherein the carrier comprises apolysaccharide gel having a viscosity between about 200,000 centipoiseto about 250,000 centipoise.
 27. The composition of claim 26, furthercomprising an additive.
 28. The composition of claim 28, wherein theadditive comprises at least one of a surfactant, a stabilizer, and a pHbuffer.
 29. The composition of claim 26, wherein the pharmaceuticallyactive agent comprises at least one of a analgesic, an antibiotic and agrowth factor.
 30. The composition of claim 26, wherein the biomaterialcomprises a material selected from the group consisting of a ceramic,polymethylmethacrylate, glass, a metal, silicone and mixtures thereof.31. The composition of claim 26, wherein the composition is implantableinto the human body, and wherein carrier maintains its viscous andelastic properties after implantation.
 32. The composition of claim 26,wherein the desired tissue site is a hard tissue site.
 33. Thecomposition of claim 26, wherein the desired tissue site is a softtissue site.
 34. A substantially dehydrated biocompatible tissueaugmentation composition, comprising: a biomaterial for augmenting adesired tissue site; a dehydrated, biocompatible, resorbable, suspendingmedium; and a pharmaceutically active agent, wherein the suspendingmedium includes a dehydrated polysaccharide gel for maintaining thebiomaterial suspended in the composition.
 35. The composition of claim35, wherein the pharmaceutically active agent comprises at least one ofa growth factor, an antibiotic and an analgesic.
 36. The composition ofclaim 35, wherein the biomaterial is selected from the group consistingof a ceramic, a plastic, and a metal.
 37. The composition of claim 37,wherein the biomaterial comprises rounded, substantially spherical,biocompatible, substantially nonresorbable, finely divided ceramicparticles.
 38. The composition of claim 38, wherein the ceramicparticles are selected from the group consisting of calcium phosphateparticles, calcium silicate particles, calcium carbonate particles andalumina particles.
 39. The composition of claim 35, further comprisingan additive.
 40. The composition of claim 35, wherein the composition iscapable cut or shaped.